(left to right) Andrea Rozo, graduate student; Hong Ruan, MD, PhD, assistant professor, Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School (RWJMS); and Ravi Vijayvargia, PhD, post doctoral fellow
Type 2 Diabetes: The Fat and Inflammation Story
by Hong Ruan
O
besity-linked type 2 diabetes, which is a growing global epidemic, presents public health challenges that require a better understanding of the underlying mechanisms that will lead to better management strategies, including the identification of new pharmacological targets.
Type 2 diabetes is characterized by elevated plasma levels of glucose and free fatty acids, which form body fat, and is associated with a cluster of abnormalities that include obesity, hypertension, elevated blood concentrations of fat and cholesterol, and proteins linked to inflammation. These abnormalities lead to atherosclerosis, resulting in cardiovascular and cerebrovascular diseases that include heart attack and stroke, renal failure, retinopathy and blindness, and nerve damage. These complications reduce quality of life and increase mortality rate, while reducing personal productivity. Type 2 diabetes poses therapeutic challenges that are not addressed by current therapies.
Type 2 diabetes: what went wrong?
Clinicians and researchers have long been puzzled by the fact that anti-diabetic medications that lower blood sugar levels often fail to prevent disease progression and its complications. This leads many to ask: “Have we chosen the right therapeutic target, and is there a root cause for the cluster of abnormalities observed in diabetes?”
Insulin resistance, i.e., the failure of insulin in ample supply to elicit biological responses in major insulin target tissues, has been widely recognized as a primary defect of obesity-linked type 2 diabetes. Insulin regulates whole body energy metabolism by coordinating the storage, mobilization, and utilization of free fatty acids and glucose in the adipose tissue, liver, and muscle. The development of insulin resistance not only has negative metabolic consequences but also contributes to the induction of a constellation of other abnormalities and subsequent failure of the pancreatic cells that produce insulin, resulting in overt diabetes. Thus, understanding the regulation of the insulin response and identification of the mechanisms that trigger insulin resistance are critical to finding new therapies.
Adipose tissue: a secretory organ with central roles in energy metabolism
Adipose tissue is a storage depot for excess energy in the form of fat. Adipose tissue releases free fatty acids (building blocks of fat) into the blood to feed the rest of the body in time of need. Fat cell function is regulated by hormones and neurotransmitters, and the view that fat cells are merely an inert storage space is changing rapidly. The molecular cloning of leptin, a hormone that controls appetite, and adiponectin, a hormone that increases fatty acid oxidation and inhibits glucose production in the liver, in 1994 and 1995, respectively, provided irrefutable evidence that adipose tissue is an endocrine organ that secretes proteins, peptides, and lipid factors with endocrine, paracrine, and autocrine activities that modulate fat cell function and whole-body insulin responsiveness. Intriguingly, adipose tissue exhibits distinct secretory profiles that change with tissue mass. For example, secretion of free fatty acids and inflammatory mediators by adipose tissue is profoundly increased in obese human subjects, whereas release of adiponectin is lower. Although the identities of the factors that trigger changes in adipose tissue secretory function in response to increased adipose tissue mass (obesity) are not known, recent findings suggest that chronic inflammation plays a pivotal role.
The Ruan Laboratory: focusing on fat and inflammation
About 10 years ago, my mentor Henry J. Pownall introduced me to Denis McGarry during his visit to Baylor. In his talk, McGarry explored the concept that conventional views on the basic mechanisms of type 2 diabetes have focused too heavily on blood sugar. He suggested that a better understanding of the root cause(s) of diabetes might be achieved if we put more emphasis on the importance of lipid metabolism. Henry also pointed out that there might be a misplaced navigation plan in finding a cure for type 2 diabetes, and he emphasized the importance of setting the course by sharing this quote with me, which, together with my other experiences, have guided my scientific career ever since: “Our plans miscarry because they have no aim. When a man does not know what harbor he is making for, no wind is the right wind.” Lucius Annaeus Seneca (4 BC – 65 AD)
My Navigation Plan: The broad goal of my laboratory is to identify the underlying cause of type 2 diabetes, the molecular mediators that link obesity to insulin resistance and type 2 diabetes, and the cellular sites and signaling pathways that are potential therapeutic targets. Our research is at the interface of medicine and biology, and can best be summed up by our attempt to address relevant medical and scientific questions. These are as follows: How are adipocyte-derived factors, especially inflammatory cytokines, involved in adipocyte gene transcription, metabolic and secretory function, and insulin sensitivity? More specifically, how do inflammatory cytokines induce insulin resistance in fat cells? What are the candidate drug targets for the ablation of the actions of inflammatory cytokines in the adipose tissue? With the answers to these questions, we can begin a rational search for the appropriate therapeutic measures.
Hong Ruan was a Howard Hughes Medical Institute Postdoctoral Fellow and a Postdoctoral Fellow of the American Diabetes Association at the Whitehead Institute for Biomedical Research. Her research has been supported by the American Diabetes Association, Pfizer Inc., and UMDNJ-Robert Wood Johnson Medical School (RWJMS). Dr. Ruan serves on the Diabetes Council of the State of New Jersey and was a recipient of an award from the American Diabetes Association as the medical honoree at the annual Rainbow Gala. She is an assistant professor, Department of Physiology and Biophysics, at RWJMS.
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